Srovnalová Alžběta, Kaplánek Robert, Kejík Zdeněk, Hajduch Jan, Gurská Soňa, Martásek Pavel, Hajdúch Marián, Džubák Petr, Jakubek Milan
Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Hněvotínská 5, Olomouc 775 15, Czech Republic.
BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, Vestec, Prague 252 50, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455, Prague 120 00, Czech Republic; Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology, University of Chemistry and Technology, Prague, Technická 5, Prague 166 28, Czech Republic.
Biomed Pharmacother. 2025 Sep;190:118404. doi: 10.1016/j.biopha.2025.118404. Epub 2025 Aug 4.
We report the design, synthesis, and biological evaluation of novel hybrid anticancer agents bearing three pharmacophores in one molecule: benzothiazole, cyclobut-2-ene-1,2-dione and hydrazone moieties. Several derivatives have demonstrated potent anticancer activity and high selectivity towards T-lymphoblastic leukaemia (CCRF-CEM) and colorectal cancer (HCT116) cell lines. The effects of in situ formed metal complexes on anticancer activity were investigated, revealing that the Fe(III) complexes of some derivatives were more active than the parental ligands, whereas the Cu(II) and Zn(II) complexes did not enhance cytotoxicity. However, compound 6 exhibited a decrease in cytotoxic activity upon the addition of iron, suggesting that the balance between extracellular and intracellular metal chelation is crucial for the anticancer activity of these compounds. Fluorescence microscopy using U2OS cells revealed the colocalization of specific derivatives with cellular components, including mitochondria (Pearson's coefficient for colocalization yielded positive correlation values of 0.85 and 0.83 for compound 6 at two concentrations), accompanied by a reduced mitochondrial membrane potential, endoplasmic reticulum vacuolization and reduction in lysosomal integrity. Moreover, cell cycle analysis revealed that compound 6 induced concentration-dependent G2/M cell cycle arrest, further contributing to its anticancer activity. These results imply the potential of these compounds to induce nonapoptotic, oncosis-like cell death. Lipinski's rule of five analysis, along with calculated drug-likeness and drug-score factors, indicates that most of these compounds have properties compatible with oral bioavailability and potential for further development. This study presents a promising new class of hybrid anticancer agents with a unique mechanism of action and favourable drug-like properties.
我们报告了新型杂合抗癌剂的设计、合成及生物学评价，该抗癌剂在一个分子中含有三个药效基团：苯并噻唑、环丁 - 2 - 烯 - 1,2 - 二酮和腙部分。几种衍生物已显示出对T淋巴细胞白血病（CCRF - CEM）和结肠直肠癌（HCT116）细胞系具有强效抗癌活性和高选择性。研究了原位形成的金属配合物对抗癌活性的影响，结果表明某些衍生物的Fe(III)配合物比母体配体更具活性，而Cu(II)和Zn(II)配合物并未增强细胞毒性。然而，化合物6在加入铁后细胞毒性活性降低，这表明细胞外和细胞内金属螯合之间的平衡对于这些化合物的抗癌活性至关重要。使用U2OS细胞的荧光显微镜检查显示特定衍生物与细胞成分共定位，包括线粒体（在两个浓度下，化合物6的共定位皮尔逊系数产生的正相关值分别为0.85和0.83），同时伴随着线粒体膜电位降低、内质网空泡化和溶酶体完整性降低。此外，细胞周期分析表明化合物6诱导浓度依赖性的G2/M期细胞周期阻滞，进一步促进了其抗癌活性。这些结果表明这些化合物具有诱导非凋亡、类胀亡细胞死亡的潜力。Lipinski的五规则分析以及计算得出的药物相似性和药物评分因子表明，这些化合物中的大多数具有与口服生物利用度兼容的性质以及进一步开发的潜力。本研究提出了一类有前景的新型杂合抗癌剂，其具有独特的作用机制和良好的类药物性质。
